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151.
152.
TcPho91 is a contractile vacuole phosphate sodium symporter that regulates phosphate and polyphosphate metabolism in Trypanosoma cruzi
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We have identified a phosphate transporter (TcPho91) localized to the bladder of the contractile vacuole complex (CVC) of Trypanosoma cruzi, the etiologic agent of Chagas disease. TcPho91 has 12 transmembrane domains, an N‐terminal regulatory SPX (named after SYG1, Pho81 and XPR1) domain and an anion permease domain. Functional expression in Xenopus laevis oocytes followed by two‐electrode voltage clamp showed that TcPho91 is a low‐affinity transporter with a Km for Pi in the millimolar range, and sodium‐dependency. Epimastigotes overexpressing TcPho91‐green fluorescent protein have significantly higher levels of pyrophosphate (PPi) and short‐chain polyphosphate (polyP), suggesting accumulation of Pi in these cells. Moreover, when overexpressing parasites were maintained in a medium with low Pi, they grew at higher rates than control parasites. Only one allele of TcPho91 in the CL strain encodes for the complete open reading frame, while the other one is truncated encoding for only the N‐terminal domain. Taking advantage of this characteristic, knockdown experiments were performed resulting in cells with reduced growth rate as well as a reduction in PPi and short‐chain polyP levels. Our results indicate that TcPho91 is a phosphate sodium symporter involved in Pi homeostasis in T. cruzi. 相似文献
153.
Muhammad Yasir Asghar Melissa Magnusson Kati Kemppainen Pramod Sukumaran Christoffer L?f Ilari Pulli Veronica Kalhori Kid T?rnquist 《The Journal of biological chemistry》2015,290(26):16116-16131
The identity of calcium channels in the thyroid is unclear. In human follicular thyroid ML-1 cancer cells, sphingolipid sphingosine 1-phosphate (S1P), through S1P receptors 1 and 3 (S1P1/S1P3), and VEGF receptor 2 (VEGFR2) stimulates migration. We show that human thyroid cells express several forms of transient receptor potential canonical (TRPC) channels, including TRPC1. In TRPC1 knockdown (TRPC1-KD) ML-1 cells, the basal and S1P-evoked invasion and migration was attenuated. Furthermore, the expression of S1P3 and VEGFR2 was significantly down-regulated. Transfecting wild-type ML-1 cells with a nonconducting TRPC1 mutant decreased S1P3 and VEGFR2 expression. In TRPC1-KD cells, receptor-operated calcium entry was decreased. To investigate whether the decreased receptor expression was due to attenuated calcium entry, cells were incubated with the calcium chelator BAPTA-AM (1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid). In these cells, and in cells where calmodulin and calmodulin-dependent kinase were blocked pharmacologically, S1P3 and VEGFR2 expression was decreased. In TRPC1-KD cells, both hypoxia-inducible factor 1α expression and the secretion and activity of MMP2 and MMP9 were attenuated, and proliferation was decreased in TRPC1-KD cells. This was due to a prolonged G1 phase of the cell cycle, a significant increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27, and a decrease in the expression of cyclin D2, cyclin D3, and CDK6. Transfecting TRPC1 to TRPC1-KD cells rescued receptor expression, migration, and proliferation. Thus, the expression of S1P3 and VEGFR2 is mediated by a calcium-dependent mechanism. TRPC1 has a crucial role in this process. This regulation is important for the invasion, migration, and proliferation of thyroid cancer cells. 相似文献
154.
155.
Chronic mTOR inhibition in mice with rapamycin alters T,B, myeloid,and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice
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Vincent Hurez Vinh Dao Aijie Liu Srilakshmi Pandeswara Jonathan Gelfond Lishi Sun Molly Bergman Carlos J. Orihuela Veronica Galvan Álvaro Padrón Justin Drerup Yang Liu Paul Hasty Zelton Dave Sharp Tyler J. Curiel 《Aging cell》2015,14(6):945-956
The mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension. 相似文献
156.
Nucci NV Marques BS Bédard S Dogan J Gledhill JM Moorman VR Peterson RW Valentine KG Wand AL Wand AJ 《Journal of biomolecular NMR》2011,50(4):421-430
Comprehensive application of solution NMR spectroscopy to studies of macromolecules remains fundamentally limited by the molecular
rotational correlation time. For proteins, molecules larger than 30 kDa require complex experimental methods, such as TROSY
in conjunction with isotopic labeling schemes that are often expensive and generally reduce the potential information available.
We have developed the reverse micelle encapsulation strategy as an alternative approach. Encapsulation of proteins within
the protective nano-scale water pool of a reverse micelle dissolved in ultra-low viscosity nonpolar solvents overcomes the
slow tumbling problem presented by large proteins. Here, we characterize the contributions from the various components of
the protein-containing reverse micelle system to the rotational correlation time of the encapsulated protein. Importantly,
we demonstrate that the protein encapsulated in the reverse micelle maintains a hydration shell comparable in size to that
seen in bulk solution. Using moderate pressures, encapsulation in ultra-low viscosity propane or ethane can be used to magnify
this advantage. We show that encapsulation in liquid ethane can be used to reduce the tumbling time of the 43 kDa maltose
binding protein from ~23 to ~10 ns. These conditions enable, for example, acquisition of TOCSY-type data resolved on the adjacent
amide NH for the 43 kDa encapsulated maltose binding protein dissolved in liquid ethane, which is typically impossible for
proteins of such size without use of extensive deuteration or the TROSY effect. 相似文献
157.
Claudia C. Soliz-Gamboa Dana? M. A. Rozendaal Greg��rio Ceccantini Veronica Angyalossy Klaas van der Borg Pieter A. Zuidema 《Trees - Structure and Function》2011,25(1):17-27
Knowledge on juvenile tree growth is crucial to understand how trees reach the canopy in tropical forests. However, long-term
data on juvenile tree growth are usually unavailable. Annual tree rings provide growth information for the entire life of
trees and their analysis has become more popular in tropical forest regions over the past decades. Nonetheless, tree ring
studies mainly deal with adult rings as the annual character of juvenile rings has been questioned. We evaluated whether juvenile
tree rings can be used for three Bolivian rainforest species. First, we characterized the rings of juvenile and adult trees
anatomically. We then evaluated the annual nature of tree rings by a combination of three indirect methods: evaluation of
synchronous growth patterns in the tree- ring series, 14C bomb peak dating and correlations with rainfall. Our results indicate that rings of juvenile and adult trees are defined
by similar ring-boundary elements. We built juvenile tree-ring chronologies and verified the ring age of several samples using
14C bomb peak dating. We found that ring width was correlated with rainfall in all species, but in different ways. In all, the
chronology, rainfall correlations and 14C dating suggest that rings in our study species are formed annually. 相似文献
158.
Peduto A Pagano B Petronzi C Massa A Esposito V Virgilio A Paduano F Trapasso F Fiorito F Florio S Giancola C Galeone A Filosa R 《Bioorganic & medicinal chemistry》2011,19(21):6419-6429
A series of trisubstituted naphthalimides have been synthesized and evaluated as telomeric G-quadruplex ligands by biophysical methods. Affinity for telomeric G-quadruplex AGGG(TTAGGG)(3) binding was first screened by fluorescence titrations. Subsequently, the interaction of the telomeric G-quadruplex with compounds showing the best affinity has been studied by isothermal titration calorimetry and UV-melting experiments. The two best compounds of the series tightly bind the telomeric quadruplex with a 2:1 drug/DNA stoichiometry. These derivatives have been further evaluated for their ability to inhibit telomerase by a TRAP assay and their pharmacological properties by treating melanoma (M14) and human lung cancer (A549) cell lines with increasing drug concentrations. A dose-dependent inhibition of cell proliferation was observed for all cellular lines during short-term treatment. 相似文献
159.
Monari E Casali C Cuoghi A Nesci J Bellei E Bergamini S Fantoni LI Natali P Morandi U Tomasi A 《Proteome science》2011,9(1):55-10
Background
Non Small Cell Lung Cancer (NSCLC) is the major cause of cancer related-death. Many patients receive diagnosis at advanced stage leading to a poor prognosis. At present, no satisfactory screening tests are available in clinical practice and the discovery and validation of new biomarkers is mandatory. Surface Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-ToF-MS) is a recent high-throughput technique used to detect new tumour markers. In this study we performed SELDI-ToF-MS analysis on serum samples treated with the ProteoMiner? kit, a combinatorial library of hexapeptide ligands coupled to beads, to reduce the wide dynamic range of protein concentration in the sample. Serum from 44 NSCLC patients and 19 healthy controls were analyzed with IMAC30-Cu and H50 ProteinChip Arrays.Results
Comparing SELDI-ToF-MS protein profiles of NSCLC patients and healthy controls, 28 protein peaks were found significantly different (p < 0.05), and were used as predictors to build decision classification trees. This statistical analysis selected 10 protein peaks in the low-mass range (2-24 kDa) and 6 in the high-mass range (40-80 kDa). The classification models for the low-mass range had a sensitivity and specificity of 70.45% (31/44) and 68.42% (13/19) for IMAC30-Cu, and 72.73% (32/44) and 73.68% (14/19) for H50 ProteinChip Arrays.Conclusions
These preliminary results suggest that SELDI-ToF-MS protein profiling of serum samples pretreated with ProteoMiner? can improve the discovery of protein peaks differentially expressed between NSCLC patients and healthy subjects, useful to build classification algorithms with high sensitivity and specificity. However, identification of the significantly different protein peaks needs further study in order to provide a better understanding of the biological nature of these potential biomarkers and their role in the underlying disease process. 相似文献160.
Recent studies demonstrate that the receptor tyrosine kinase RET is overexpressed in a subset of ER-positive breast cancers and that crosstalk between RET and ER is important in responses to endocrine therapy. The development of small molecular inhibitors that target RET allows the opportunity to consider combination therapies as a strategy to improve response to treatment and to prevent and combat endocrine resistance. This review discusses: (i) the current knowledge about RET, its co-receptors and ligands in breast cancer; (ii) the breast cancer clinical trials involving agents that target RET; and (iii) the challenges that remain in terms of specificity of available inhibitors and in understanding the complex molecular mechanisms that underlie the resistance to endocrine therapy. 相似文献